The present invention relates to an apparatus for the treatment of blood by extracorporeal circulation and to a process of manufacture of this apparatus.
Apparatuses for the treatment of blood by extracorporeal circulation are employed in various medical or paramedical applications such as: treatment of renal insufficiency by dialysis. or haemofiltration, plasmapheresis and aphaeresis with therapeutic and nontherapeutic aim, blood oxygenation, immunopurification, and the like.
A common feature of all these apparatuses is that they comprise a blood compartment provided with two accesses, in which, during the treatment in question the patient""s blood is circulated. To do this, a blood withdrawal line is connected between a blood vessel of the patient and an access, employed as entry, of the blood compartment; a blood return line is connected between the other access of the blood compartment, employed as exit, and a blood vessel of the patient; and the patient""s blood is circulated in this extracorporeal circuit looped onto the patient, by means of a pump, usually placed in the withdrawal line.
The blood compartment of these apparatuses is generally bounded by a portion of the walls of a casing of the apparatus and by a wall of an active member of the apparatus, by means of which the treatment of blood is performed. By way of example, in a dialyser containing hollow fibres, the blood compartment is bounded by the interior of the fibres of a bundle of hollow fibres, constituting a semipermeable membrane, by the external surface of the discs of adhesive employed for attaching the bundle of fibres to the two ends of a tubular casing of the apparatus, and by two end fittings secured to each end of the casing.
All the materials employed in the manufacture of these apparatuses are chosen to be as biocompatible as possible, so that the reactions (coagulation in particular) which take place when the blood comes into contact with a foreign material do not take place or take place at relatively benign levels.
It is known to treat, in bulk or at the surface, the materials intended to be in contact with blood in order to improve their biocompatibility. The known treatments take place either during the manufacture of some part or other of an apparatus (bulk treatment), or after the various parts of the apparatus have been assembled and before sterillization of the apparatus, or, extemporaneously, just before the apparatus is employed.
A problem which is particularly tough to solve arises when attempts are made to improve the biocompatibility of the active member of an apparatus (for example a dialysis membrane) while conforming to the following conditions:
1) the choice of the substance employed for the treatment and the treatment methods must result in the modification of a known active member, this modification having the effect of improving the biocompatibility of the active member while preserving all the known qualities (for example, in the case of a dialysis/haemofiltration membrane: diffusive and convective transfer performance, adsorption capacity for undesirable substances, and the like);
2) sterillization of the apparatus must not affect the treatment;
3) the treatment must not require any special handling by the user.
The objective of the invention is to propose a process for the manufacture of an apparatus which satisfies these conditions.
More specifically, the objective of the invention is to propose a process of manufacture of an apparatus satisfying the conditions specified above and in which the active member, before treatment, has negative charges at the surface. When blood comes into contact with a negatively charged surface, it is the site of a biological phenomenon called activation of the contact phase, which manifests itself in the generation of active substances, kallikrein and factor XIIa, from inactive substances, prekallikrein and factor XII.
The activation of the contact phase is benign in itself, but when it takes place simultaneously with some perturbing factors (taking of hypotensive medications of IEC type by the patient, dilution of the blood entering the apparatus filled with saline solution, accompanying lowering of the pH) it seems to be the source of undesirable so-called anaphylactoid reactions which manifest themselves a few minutes after the beginning of the treatment as various symptoms, including an overall feeling of hotness, numbness of the fingers, the lips or the tongue, panting, nausea and laryngeal oedema. It should be remembered that anaphylactoid reactions are not exclusively linked with the use of medical apparatuses in which the blood compartment has a negatively charged inner surface. These reactions have been noted with exchangers which have membranes of different chemical compositions, sometimes when first employed, sometimes after several utilizations when the exchangers, instead of being discarded after a single use, are used again many times and are recycled after each use. An example of an exchange in which a first use has been accompanied by an undesirable reaction is a dialyser which has a polymethyl methacrylate and polyacrylonitrile membrane. Reactions associated with the reuse of dialysers with a cellulose acetate and polysulphone membrane have been just as well documented (see xe2x80x9cAnaphylactoid reactions associated with reuse of hollow-fiber hemodialyzers and ACE inhibitorsxe2x80x9d in Kidney International, vol. 42 (1992), pp. 1232-1237).
There is provided, in accordance with one aspect of the invention, a process for improving the biocompatibility of an apparatus for the treatment of blood or plasma by extracorporeal circulation. The apparatus has a compartment for the circulation of blood provided with two accesses. In the process, a determined quantity of a substance is deposited in the blood compartment at at least one of the accesses. The substance is deposited in a form such that the substance is capable of undergoing, substantially without deterioration, an irradiation capable of sterilizing the apparatus.
The substance is capable of dissolving in an aqueous solution and of being durably bonded to an inner surface of the blood compartment in order to increase the biocompatibility of the apparatus. The quantity of substance is determined such that the circulation of a determined volume of aqueous solution through the blood compartment, starting from the access where the substance has been deposited, should result in the formation of at least one molecular layer of the substance, by durable bonding, to the inner surface of the blood compartment.
The process also includes sterilizing the apparatus and, before the utilization of the apparatus, circulating a determined volume of aqueous solution through the blood compartment. The circulation of aqueous solution starts from the access where the substance has been deposited, so as to carry the substance into contact with the inner surface of the blood compartment and to cause the formation of at least one durable molecular layer of the substance on the inner surface of the blood compartment.
Within the meaning of the invention, the ability to dissolve in an aqueous solution, which is a characteristic of the substance, must be understood as a function of the objective to be met. That is at the outcome of the process, at least one molecular layer of the substance is bonded to the inner surface to be treated of the blood compartment. In addition, when it would be undesirable that the substance should be introduced into the patient""s blood, it is necessary that at the outcome of the process all the substance should have been dissolved and that no residue should remain in the blood compartment. In other words, this ability comprises both the physical ability to dissolve in an aqueous solution and a speed of dissolution, which depends on a number of parameters: volume of aqueous solution employed, temperature of the aqueous solution, and flow rate of the aqueous solution in the blood compartment. If these parameters are fixed, for example by deciding that the last stage of the process will be carried out immediately before the use of the apparatus during the procedure for starting up (xe2x80x9cprimingxe2x80x9d) the apparatus, then the substance must be chosen, among other criteria, so that the objective of the invention can be met by circulating through the blood compartment, for example, two liters of physiological saline at ambient temperature (20xc2x0 C. to 24xc2x0 C.) at a flow rate of 200 ml/min (conventional conditions for starting up a dialyser in a dialysis centre).
The process has two major advantages: on the one hand, the surface modified by the substance is obtained only after sterillization of the apparatus, with the result that this modified, biocompatible surface does not run the risk of being damaged by a highly energetic sterillization like sterillization using xcex3 irradiation; on the other hand, when the aqueous solution employed is the solution for starting up the exchanger, the utilization of the apparatus by the user is exactly identical with that of any apparatus of the same type.
According to an alternative form of the invention, in an apparatus in which the blood compartment has two symmetrical accesses, the determined quantity of substance is deposited at each access so that, whatever the direction of subsequent circulation of the aqueous solution through the blood compartment, a molecular layer of the substance is formed on the inner surface to be treated.
Another subject of the invention id a process of manufacture of an apparatus for the treatment of blood or plasma by extracorporeal circulation. The apparatus has a compartment for the circulation of blood provided with two accesses. The process includes, before a stage of sterillization of the apparatus, the step of depositing in the blood compartment, at at least one of the accesses, a determined quantity of a substance in a form such that the substance is capable of undergoing, substantially without deterioration, an irradiation capable of sterilizing the apparatus.
The substance is capable of dissolving in an aqueous solution and of durably bonding to an inner surface of the blood compartment in order to increase the biocompatibility of the apparatus. The quantity of substance is determined such that the circulation of a determined volume of aqueous solution through the blood compartment, starting from the access where the substance has been deposited, should result in the formation, by durable bonding, of at least one molecular layer of the substance on the inner surface of the blood compartment.
This process has the advantage of being very easy to apply industrially.
Another subject of the invention, is an apparatus for the treatment of blood or of plasma resulting from the use of the process of manufacture described above.
According to an alternative form of the invention, the surface to be treated has negative charges and the substance is cationic, with the result that a molecular layer of the surface masks the negative charges of the surface.
In one embodiment of the invention the apparatus is a haemodialyser/haemofilter provided with a membrane manufactured from a copolymer of acrylonitrile and of sodium methallylsulphonate (membrane known under the trade name AN69). The substance chosen for improving the biocompatibility of this membrane is polyethyleneimine (PEI) which has a molecular mass (measured by light scattering) of between approximately 10 and approximately 2000 k dalton. The quantity of PEI (molecular mass 25 k dalton) deposited at one or each blood access is preferably between approximately 5 and 10 mg per m2 of membrane intended to be in contact with the blood.